Novel 9, 11-disubstituted estratriene derivatives



llited States Patent Office Patented Pele. 5, 19353 3,976,829 NOVEL 9,1l DISUlESTHUiED 'ESIRATRlENE DERIVATIVES Hans Reimann, Bloomfield, and Cecil H. Robinson, Cedar Grove, N..l., assignors to Scheringtforporation, Bloomfield, NJ a corporation of New Jersey No Drawing. Filed Sept. 15, 1961. SeiuNo. 138,271 20 Claims. (CI. Zed-397.45)

This invention is concerned with novel, therapeutically active 9,11-disubstituted estrogens and methods for their manufacture. More specifically, this invention relates to novel 9a,llB-disubstituted-1,3,5(10)-estratrienes and analogs thereof, which possess estrogenic activity.

Included among the novel estratrienes of our invention are compounds having the following structural formula:

wherein W is a member of the group consisting of H and methyl; R is a member of the group consisting of H, lower alkyl, and an acid radical of an acid of the group consisting of sulfuric acid and carboxylic acids having up to 8 carbon atoms; X is a halogen having an atomic weight less than 100; Y is a member of the group consisting of keto,

and

R being a member of the group consisting of H and lower alkanoyl, X being a halogen having an atomic weight less than 40 and when Y is X must have an atomic weight greater thant20v; and Z is at-member .of the group consisting of keto,

lower alkyl and wherein R is as heretofore defined.

By lower alkyl is meant a hydrocarbon radical having up to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

Illustrative of the carboxylic acid esters contemplated are lower alkanoates such as acetate, propionate, butyrate, valerate, caproate, and t-butyl-acetate; aroyl esters such .as benzoate and toluate, and esters from dibasic organic acids such as succinate, phthalate and sulfobenzoate. Also included in the'term acid radical 2 are the alkali metal salts of the dibasic carboxylic acid esters such as, for example, the 3,17-di-sodium hemisuccinate of 9ot-chloro-ll-ketoestradiol.

The above definition of the novel compounds of our invention should not be strictly construed but rather may be considered to admit the presence of other substituents on the steroid nucleus, particularly at positions 6 and 16, such as 6ot-methyl, 6a-fiuoro, 6a-chloro, 16ahydroxy, c-21CY10XY, 16-methyl and lfi-halogen analogs thereof. This modification depends solely on the choice of starting material employed, which in the instant case would involve the employment of a 9(l1)-dehydroestratriene starting steroid possessing the desired substituent in the positions indicated, which substituents are introduced by methods known in the art.

The novel estratrienes defined by the general formula possess estrogenic activity and thus are therapeutically useful in the treatment of the menopausal syndrone, in female hypogonadism, functional uterine bleeding, and post partum breast engorgement. The novel 9,11-disubstituted estratrienes are also useful for the lowering of blood cholesterol, and may also be used in cosmetics for topical application. Our novel estrogens may be administered parenterally in aqueous or oil suspension for intra-muscular injection or in pellet form for subcutaneous implantation; and orally in tablet form. Our novel 9,11-disubstituted estrogens may be used in the usual dosage forms and in the same manner as other known estrogens such as Estinyl (l7e-ethinylestradiol) and Progynon (estradiol).

Among the 9,11-disubstituted-estratrienes of our invention are 9a,l1,B-dihalogeno derivatives such as 90:,115- dichloroestrone (i.e., 9a,11p-dichloro-1,3,5 {l0)-estratriene-3-ol-l7-one) and the 3-acetate and 3-benzoate esters thereof, 9e,llfl-dichlorod7a-ethinylestradiol B-benzoate (i.e., 9o 1lB-dichloro-Na-ethinyl-1,3,5t10)-estratri one-3,17B-diol B-benzoate), 9a-chloro-lldfiuoroestradiol diacetate, 9oc-bromo-llB-fluoroestrone 3-methyl ether, 1,l7a-dirnethyl-9a,llfi-dichloroestradiol 3-methyl ether, l-methyl-9m-fiuoro-llB-chloroestrone I i-methyl ether; 9w halogeno-l l-keto derivatives such as 9e-bromo-ll-ketoestrone, 9u-chloro-1l-ketoestradiol, 9a-fluoro-11-ketoestrone acetate, l-rnethyl 9wbromo-l1 keto-l'ia-ethinyl estradiol S-methyl ether and the 17-acetate thereof; and -9oz,ll,8-halohydrins and esters thereof such as 9ot-bromollfl-hydroxyestrone S-acetate, 9ot-chloro-llfi-hydroxyestradiol 3,17-diacetate, 9a-chloro-llfi-formyloxyestradiol 3,17-tliacetate, l -methyl-9a-fiuoro-l l s-hydroxy-lh-ethinylestradiol 3-acetate and 1,17u-dirnethyl-9e-bromo-11(3- hydroxyestradiol 3-methyl ether.

Of the novel, therapeutically active estratrienes of our invention the l-desmethylestratrieues are preferred over the l-methylestratrienes and, of the l-desmethylestratrienes, the 9a,11fl-dihalogenoand 9e-fluo-ro-lll3-hydroxy derivatives are particularly valuable, such as, for example, 90,llfl-dichloroestrone, 9e-chloro-llfi-iluoroestrone, 9a,1lfi-dichloro-l7e-ethinylestradiol, 9e-chloro-11fl-fiuoro-l7a-ethinylestradiol, and esters thereof and 9oc-ill10l0- l l B-hydroxyestrone.

The novel 9,1l-disubstituted-estratrienes of our invention are prepared from the corresponding 1,3,5(l0),9(1l)- estratetraene derivatives by the addition of halogen, hypohalous acid, or halogen acylate to the 9(ll)-double bond, utilizing techniques analogous to those known in the art. Some 1,3,5 (lO),9(ll)-estratetraene starting compounds are known, such as 9(ll)-dehydroestrone, the 3- methyl ether, S-acetate ester, and derivatives thereof, as well as 9(ll)-dehydroestradiol and its S-methyl ether. Other 9(1l)-dehydro starting compounds such as methyl-9 (1l) dehydroestradiol and 17a ethinyl 9(l1)- dehydroestradiol are readily prepared from 9(1l)-dehyarr/asses d? droestrone by known methods. For example, 9(11)- dehydroestrone is readily transformed to Hot-methyl- 9(ll)-dehydroestradiol by the Well known Grignard re agent methyl magnesium iodide. By utilizing other lower alkyl Grignard reagents such as ethyl magnesium bromide, 9(ll)-dehydroestrone may be converted to other 17alower alkyl derivatives, e. g., 17 L-l1hy1-9( 1 l -dehydroestradiol. Similarly, 9(1l)-dehydroestrone may be transformed to 17a-ethinylestradiol by means of sodium or potassium acetylide. Those 9(ll)-dehydroestrone and 9(11)-dehydroestradiol starting compounds having a 1- methyl substituent are prepared as described in copending application of Reimann, Serial No. 138,270, filed on even date with the instant application. By this method, a steroidal 3-keto-1,4-,9(1l)-triene of the pregnane or androstane series is heated with a strong acid catalyst (e.g., ptoluene-sulfonic acid or trifiuoroacetic anhydride) in an acid solvent, preferably a lower alkanoic acid or anhydride (e.g., acetic acid, or acetic anhydride) whereby the 3- keto-l,4-dehydro-A-ring is aromatized to give the corresponding l-methyl-3-hydroxy-1,3,5 -estratriene. For example, when l,4,9(11)androstatriene 3,17 dione in acetic acid in the presence of p-toluenesulfonic acid is heated on the steam bath there is formed l-methyl-9(1l)- dehydroestrone (1-methyl-1,3,5(10),9(1l)-estratetraene- 3-0l-17-one) in the manufacture of our novel 9,11-disubstituted estratriene derivatives, the additions to the 9(1l)-double bond of the starting 1,3,5(l0),9(l1)-estratetraenes are carried out according to procedures similar to those described in the literature. Thus, when preparing the 90:,11fi3- dihalogeno estratrienes of our invention, i.e., the 90,1l5- dichloro-, 9a-bromo-1lfi-chlord, 9d-bromo-llp-fluoro-, and 9cr-cnloro-llfi-fiuoro-derivatives, there is utilized a halogen or halogen donor such as N-bromoacetamide, chlorine, or N-chlorosuccinimide in the presence of a halide anion such as chloride or fluoride according to procedures similar to those described in U.S. Patent No. 2,- 894,963 and in J. Org. Chem. 26, 866 (1961). Thus, for example, when 9(l1)-dehydroestrone 3-nethyl ether in carbon tetrachloride is reacted with chlorine in the presence of pyridine there is obtained 9a,1lfl-dichloroestrone 3-rnethyl ether; whereas when hydrogen fluoride and N- chlorosuccinimide are the reagents utilized, the compound 9a-cl1loro-1lfi-fluoroestrone 3-rnethyl ether is produced. Similarly, when 9(ll)-dehydroestradiol diacetate in diethylacetic acid is reacted with N-bromoacetamide and hydrogen fluoride, 9zx-bromo-1lfi-fiuoroestradiol diacetate is formed, whereas reaction With lithium chloride/N- bromoacetamide/anhydrous hydrogen chloride gives 906- bromo 11 6 chloroestradiol diacetate. When preparing 9,11-dihalogenoestratriene derivatives, it is preferable to have any primary or secondary hydroxyl groups protected prior to halogenation (such as by preparing an ester, e.g., an acetate by reaction with acetic anhydride and pyridine). Thus, for example, 1,17ot-dimethyl-9(11)-dehydroestradiol is converted to the corresponding 3-acetate ester by reaction with acetic anhydride in pyridine prior to halogenation with hydrogen fluoride and N-chlorosuccinimide. The resultant product, 1,17a dimethyl 9a chloro 11 3- fiuoroestradiol 3-acetate, may then be hydrolyzed to the 3-01 by conventional methods such as with methanolic potassium carbonate.

The novel 9a halogeno 1l alkanoyloxy-l,3,5(l0)- estratrienes of our invention are derived from the corresponding 9(11)-dehydroestrogens by reaction with a halogen donor such as N-bromoacetamide or N-chlorosuccinimide in the presence of a source of acylate such as formic, acetic, propionic acids or the like according to procedures similar to those described by Robinson et al. I. Am. Chem. Soc. 81, 2195 (1959). Thus, for example, 9(l1)-dehydroestradiol diacetate when reacted with N- hromoacetamide and lithium acetate in glacial acetic acid yields the corresponding Qa-bromo-llfl-atcetoxy derivative, i.e., 9a-bromo-1lfi-acetoxyestradiol diacetate. Similarly,

9(11) dehydroestradiol diacetate upon reaction with formic acid containing sodium formate and N-chlorosuccinimide with one equivalent of anhydrous hydrogen chloride is converted to 9a-chloro-1lp-formyloxyestradiol diacetate. The 9a-fluoro-11fi-acyloxy derivatives are most conveniently obtained by esterification of the corresponding ll-hydroxy derivatives such as by heating with the desired acid in the presence of trifiuoroacetic anhydride. For example, iiuoro llfl hydroxyestrone 3 acetate heated with glacial acetic acid and trifiuoroacetic anhydride is converted to 90 fiuoro 11B acetoxyestrone 3- acetate.

lntroduction of the 9a-halogeno-116-hydroxy groups into the 9(ll)-dehydroestratriene starting compounds of our process may be accomplished by the use of a halogen donor such as N-hromosuccinimide in the presence of water and a strong acid such as perchloric acid. Thus 9(1l)-dehydroestrone 3-acetate reacted with N-bromosuocinimide and perchloric acid yields a novel estratriene of our invention, namely 9et-bromo-llfl-hydroxyestrone 3-acetate. Other 9cx-halogeno derivatives are obtained from the corresponding hromohydrin such as the aforementioned, by refluxing with mild alkali, e.g., potassium acetate in acetone, to form the corresponding 9,8,11,8- oxido derivatives, e.g., 96,115-oxidoestrone 3-acetate. The oxido intermediates are then reacted with hydrogen fluoride in chloroform with or without ethanol and/or tetrahydrofuran to form fiuorohydrins, e.g., 9a-fl110T0-l 118- hydroxyestrone 3-acetate. Similarly, the substitution of anhydrous hydrogen chloride for hydrogen fluoride in this reaction results in the production of the corresponding 9cz-Chl010 derivatives, e.g., 9a-chloro-1lfi-hydroxyestrone 3-acetate.

The novel 9ot-ha1ogeno-1l-keto-estratrienes of our invention are conveniently derived by oxidation of the corresponding ll-hydroxy derivative using an oxidizing agent such as chromic acid. Thus, 1-methyl-9a-brom0-l1fihydroxyestradiol 3,17-diacetate upon oxidation with chromic acid yields an ll-keto compound of our invention, namely, 1-methyl-9et-bromo-11-ketoestradiol 3,17- diacetate. Alternatively, 9oz-br0m0-l1 ,B-hydroxyestrone', 9ot-bromo-ll-ketoestrone and 95,11,8-oxidoestrone may by prepared from the corresponding l9-nor-4-androstene 3-one by microbiological 1,2-dehydrogenation, for example, with Corynebacterium simplex.

In the preparation of our novel 9,11.-disubstituted estrogens, it is preferable to carry out all desired modifications of the molecule prior to addition to the 9(11)- double bond. Thus, it is preferable, for example, to convert 9(l1)-dehydroestrone by means of ethyl magnesium bromide to 17a-ethyl-9(11)-dehydr0estradiol followed by esterification at the 3-position by means of acetic an hydride in pyridine prior to halogenation, for example, with chlorine in carbon tetrachloride to give the novel compound of this invention, 9e,1lfl-dichloro-l7ot-ethylestrad-iol 3-acetate. It is to be noted that the primary and secondary hydroxyl groups are preferentially protected such as by ester groups during all the addition reactions. When preparing the 17a-ethiny1 analogs, how' ever, it is usually preferable to carry out the ethinatior'r reaction after the substituents have been introduced at C9 and C-1 1. For example, 9OL-ChlO1'O-11 fl-fluorocstrone 3-methyl ether of our invention is converted to another novel estratriene by reaction with sodium acetylide to give 9a-chloro-1LB-fiuoro-17a-ethinylestradi0l B-methyl ether.

The following are examples which illustrate our inven tion. It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art; the invention is therefore to be limited only by the scope of the appended claims. I l i 5 EXAMPLE -1 9(11 -Dehydrestr0ne Acetate To a solution of 1.0 g. of 9(11)-dehydroestrone in ml. of pyridine is added 0.8 ml. of acetic anhydride. The mixture is allowed to stand at room temperature for 3 hours. It is then poured into ice water and the resulting precipitate is filtered, Washed with water, dried, and crystallized from ethyl acetate-ether and ethyl acetatepentane to give 9(11)-dehydroestrone acetate, MP. 115-- l17 C.; [00 4-23 3 (CHC1 M52 257 m (e 17,100)

Similarly, by substituting other lower alkanoic acid anhydrides, such as valeric and caprylic anhydrides, for acetic anhydride in the procedure of this example there is obtained 9(ll)-dehydroestrone valerate and 9 (11)-dehydroestrone caprylate, respectively.

EXAMPLE 2 9(11 )-Deltydroestr0ne Benzoate To a solution of 784 mg. of 9(ll)-dehydroestrone in ml. of pyridine is added 1 ml. of benzoyl chloride. The mixture is allowed to stand at room temperature overnight, and is then poured into ice-water, and stirred for 20 minutes. The resulting precipitate is filtered, Washed, dried, and crystallized from acetone-hexane to give 9(ll)-dehydroestrone benzoate, MP. 232-234 C.;

[eth l-238 (CHCl Similarly by substituting other acid chlorides such as m-toluyl chloride for benzoyl chloride in the procedure of this example there is obtained 9(11)-dehydroestrone m-toluate.

EXAMPLE 3 9a,]1 fl-Diclzlaroestrcne Acetate To a solution of 250 mg. of 9(11)-dehydroestrone acetate and 1.0 g. of lithium chloride in 12 m1. of acetic acid is added 114 mg. of 98% N-chlorosuccinirnide and 0.25 ml. of a 7 N solution of hydrogen chloride in tetrahydrofuran. The mixture is allowed to stir in the dark for 20 minutes, then poured into ice water. The resulting precipitate is filtered, washed, dried and crystallized from methylene chloride-pentane to give 9a,l1l3-dichloroestrone acetate, MP. l61l69 C. dec.; [0:1 +13 .(CHCl EXAMPLE 4 Qua-Bron: 0-1 1 ,B-Hydroxyeslrone A cetate EXAMPLE 5 9e-Brom0-1 1 -Ket0estrone A sample of 4.05 g. of 9a-bromo-11-keto-l9-nor-4- -androstene-3,l7-dione is subjected to the action of a culture of Corynebacterium simplex (ATCC 6946) in a manner similar to those given in US, Patent 2,837,464 as follows:

From a solution of 30 g. of yeast extract (Difco) in 3.0 l. of tap water containing 13.2 g. of potassium dihydrogen phosphate and 26.4 g. of disodium hydrogen phosphate (pH of the solution 6.9) 27 portions of 100 ml. each are withdrawn, placed in 300 ml. of Erlenmeyer flasks and sterilizedby autoclaving for 15 minutes at 15 lb. steam pressure (120 C). After autoclaving and cooling of the broth one ml. of a suspension of Corynebacterizmz simplex (ATCC 6946) is placed in each flask. The flasks are then shaken on a shake table at 220 r.p.m. and 28 C. for 24 hours.

In each of 27 Erlenmeyer flasks are placed 150 mg. of 9st-bromo-ll'keto-l9-nor-4-androstene-3,l7 dione. The flasks and contents are then sterilized for 15 minutes at 15 lb. steam pressure (120 C.). To each flask is then added 5.0 ml. of ethanol. The 24-hour bacterial culture is then transferred aseptically and the resulting suspensions are shaken on a shake table at 220 rpm. and 28 C. for 48 hours. The final pH is 7.2.

The contents of all the flasks are combined and extracted with a total of 9.0 l. of chloroform in three equal portions. The combined extracts are then concentrated to a residue which is crystallized from methylene chloride-pentane to give 9a-bromo-11-ketoestrone.

EXAMPLE 6 9a-Fluar0-J Jfi-Hyclroxyestrone 3-A cetate and 9ot-Chl0r0- 1 1 fl-Hydroxyestrone .3-A cetate A. 9fl,11,6-0xid0estr0ne acetateib a solution of 150 mg. of 9ot-bromo-llfi-hydroxyestrone acetate: in 10 ml. of acetone, is added 300 mg. of potassium acetate. The mixture is heated under reflux for 17 hours, then poured into ice-Water. A precipitate separates which is filtered, Washed with water, dried and crystallized from acetonehexane to give 9l3,ll,B-oxid0estrone acetate. The Beilstein test done on a sample of this compound for the presence of halogen is negative.

In a similar manner, the valerate and caprylate esters of 9ot-bromo-llB-hydroxyestrone are converted to 95,1113- oxidoestrone valerate and 95,11,6-oxidoestrone caprylate, respectively.

Alternatively, the compound of this example is prepared by subjecting 500 mg. of 95,11fl-oxidod9-nor-4- androstene-3,l7-dione to the action of Cornynebaczerium simplex (ATCC 6946) in the manner of Example 5 yielding 95,11B-oxidoestrone which is acetylated with acetic anhydride in pyridine according to the procedure of Example 1.

B. 9oc-flu0r0-1Ld-hydroxyesirone 3acetate..-A solution of 500 mg. of 96,11,8-oxidoestrone acetate in 20 ml. of methylene chloride is cooled in an ice-bath and 2 ml. of 48% aqueous hydrofluoric acid is added with stirring. The mixture is vigorously stirred in the cold for 3 hours, then poured into cold aqueous sodium bicarbonate solution. The organic layer is separated, washed with Water and concentrated in vacuo to a residue which is crystallized from acetone-hexane to give 9a-fiuoro-l1B-hydroxyestrone 3-acetate.

Similarly, the valerate and caprylate esters of 95,1113- oxidoestrone are converted to 9ot-fluoro-1l 3-hydroxyestrone valerate and a iluoro 11p hydroxyestrone caprylate, respectively.

C. 9ot-chl0r0-1lfl-hydroxyestmne 3-acemte.-To'a solution of mg. of 95,1lB-oxidoestrone acetate in 10 ml. of chloroform is added anhydrous hydrogen chloride gas at -20 C. for 3 minutes. The reaction mixture 'is chilled for two hours, then extracted with aqueous sodium acetate. The organic solution is then concentrated in vacuo to a residue which is crystallized from methylene chloride-pentane to give 9ct-chloro-llfi-hydroxyestrone 3- acetate.

EXAMPLE 7 Qa-Flttoro-l J ,d-A cetoxyestrone S-Acetate A solution of 450 mg. or" 9a-tluorollfi-hydroxyestrone 3-acetate in 5 m1. of glacial acetic acid and 1 ml. of trilluoroacetic anhydride is heated on the steam bath for 30 minutes. The reaction mixture is then poured into icewaterand the resuitantprecipitate filtered, washed, dried,

and crystallized from acetone-hexane to give 9a-fiuoro- 11 ,B-acetoxyestrone 3-acetate.

EXAMPLE 8 Qua-F [Moro-1 1 -Ketestr0ne Acetate To a solution of 100 mg. of 9a-fiuoro-11B-hydroxyestrone S-acetate in ml. of acetone is added 0.2 ml. of chromic acid-sulfuric acid reagent (266 mg. chromic acid/ml.). The mixture is left at room temperature for 2 hours, then the excess reagent is destroyed by the addition of a small amount of methanol and the solution is diluted with Water. The resulting precipitate is filtered, washed, dried, and crystallized from acetone-hexane to give 9a-fluoro-l1-ketoestrone acetate.

EXAMPLE 9 9a,] 1 ,B-Dichloroestrone Benzoaze A solution of 500 mg. of 9(11)-dehydroestrone benzoate (the compound of Example 2) in 25 ml. of carbon tetrachloride and 0.4 ml. of pyridine is cooled to -20 C. and 0.78 ml. of a solution of chlorine in carbon tetrachloride (122 mg. Cl /ml.) is added. The mixture is stirred at 20 C. for 30 minutes, then allowed to Warm to room temperature. Sufficient methylene chloride is added to give a clear solution which is then allowed to stand overnight. The solution is then concentrated in vacuo to a small volume. A precipitate separates which is filtered and crystallized from methylene chloride-pentane to give 9a,llfi-dichloroestrone benzoate M.P. 136- 143 C. dec.; [uJ +10.l (dioxane).

Similarly, the m-toluate ester of 9(l1)-dehydroestrone is reacted with chlorine in carbon tetrachloride to give 90:,11fi-di6hl01068t10115 m-toluate.

EXAMPLE 10 17ot-Ezhinyl-9a,1lfi-Dichloroestradiol .i-Benzoate 1.5 ml. of 17% sodium acetylide in xylene is centri fuged, then the xylene is decanted and 2 ml. of dimethylsulfoxide added. The resultant suspension of sodium acetylide in dimethylsulfoxide is added to a solution of 250 mg. of 9ct,llfi-dihl01"06$tf0fl6 benzoate in 6 ml. of dimethylsulfoxide. The reaction mixture is stirred at C. for 10 minutes, then poured into ice water. The resulting precipitate is filtered, washed, dried and chromatographed on silica gel. Fractions are eluted with hexaneether mixtures and those fractions combined which do not show the 17-keto band in the infrared. Crystallization of these fractions from methylene chloride-pentane gives 17a-ethinyl-9a,1lB-dichloroestradiol 3benzoate.

EXAMPLE 11 9 l1 -Dehy droestradiol Diacetate A. 9(11)-dehydroestradi0l.-To a solution of 3.0 g. of 9(ll)-dehydroestro-ne in 300 ml. of methanol, chilled in ice, is added 1.0 g. of sodium borohydride. The solution is stirred at room temperature for 100 minutes, then is poured into ice-Water and the solution acidified with acetic acid. The resulting precipitate is filtered, washed with water, and crystallized from acetone-hexane to give 9(ll)-dehydroestradiol, MP. 191-193 C.

B. 9(11)-dehydroestmdiol diacetme-A solution of 3.0 g. of 9(ll)-dehydroestradiol in ml. of pyridine and 3 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. The reaction mixture is then poured into ice-water. A solid separates, which is filtered, Washed with water, dried, and crystallized from acetonehexane to give 9(l1)-dehydroestradiol diacetate, M.P. 152453" C.; [0;] +88.4 (dioxane);

By substituting other acid anhydrides such as caproic and propionic anhydridcs for acetic anhydride in the groove procedure, there is obtained the corresponding diacrea e s acylate, i.e. the dicaproate and dipropionate, respectively, of 9 1 l -dehydroestradiol.

EXAMPLE 12 9 (11 -Dehydr0estradiol Dibenzoate To a solution of 800 mg. 9(11)-dehydroestradiol in 10 ml. of pyridine is added 1 ml. of benzoyl chloride. The mixture is kept at room temperature for 16 hours, then is poured into ice-Water and stirred for 1 hour. The resulting precipitate is filtered and crystallized from methylene chloride-pentane to give 9(ll)-dehydroestradiol dibenzoate, Ml. 185-187 C.

EXAMPLE 13 9a-Brom0-1lfl-Hydroxyesiradiol 3,1 7-Diacetate To a solution of 500 mg. of 9(11)-dehydroestradiol diacetate in 50 ml. of dioxane is added 210 mg. of N- bromo-acetamide, 5.0 ml. of Water and 2.0 ml. of 1.5 N perchloric acid. The mixture is stirred in the dark at room temperature for 2.5 hours, then poured into icewater. A gummy precipitate separates which is dissolved in methylene chloride, and crystallized from methylene chloride-pentane to give 9otbromo-1lfl-hydroxyestradiol 3,17-diacetate, MP. 119-124 C. dec.

Similarly, the dicaproate and dipropionate esters of 9(11)-dehydroestr0ne may be reacted with N-bromoacetamide according to the above procedure to give 9a-brom0- llfi-hydroxyestradiol 3,17-dicaproate and 9a-hrorno-115- hydroxyestradiol 3,17-dipropionate, respectively.

EXAMPLE 14 9a-Flzt0r0-11,8Hydroxyestradi0l 3,17-Diacetate A. 95, llfl-oxidoestraa'iol diacetate.-9ot-hromo-11B- hydroxyestradiol 3,17-diacetate mg.) is treated with potassium acetate in acetone according to the procedure of Example 6A. The resultant product is crystallized from acetone-hexane to give 9,6,11,8-oxidoestradiol diacetate, Ml. 122124 C.

B. 9a fluOr -IJfi-hydroxyestradiol 3,17-diacetate.A sample of 200 mg. of 9,8,11,6-oxidoestradiol diacetate is allowed to react with hydrofluoric acid according to the procedure of Example 613. The resultant product is isolated as described and crystallized from acetone-hexane to give 9u-fluoro-llfi-hydroxyestradiol 3,l7diacetate.

Similarly, 95,11/3-oxidoestradiol dicaproate and 96-11(3- oxidoestradiol dipropionate (prepared from the corresponding ester of Qa-bromo-llfi-hydroxyestradiol in the manner of Example 14A) are reacted With hydrofluoric acid to give 9a-fiuoro-lIB-hydroxyestradiol 3,17-dicaproate and 9ot-fluoro-llfi-hydroxyestradiol 3,1l-dipropionate, respectively.

EXAMPLE 15 9oc-Chl0r0-1 1 B-Hydroxy estradiol 3,] 7-D iacezate To a solution of 250 mg. of 9(l1)-dehydroestradiol diacetate in 25 ml. of dioxane is added 100 mg. of N-chlorosuccinimide, 2.5 ml. of water and 1.0 ml. of 1.5 N perchloric acid. The reaction mixture is stirred in the dark for 48 hours, then poured into ice-water. The resultant gummy precipitate is dissolved in methylene chloride and crystallized by the addition of cold pentane to give 900- chloro-l l/3-hydroxyestradiol 3,17-diacetate.

A-ternatively, a solution of 100 mg. of 95,11,8-oxidoestradiol diacetate in 10 ml. of chloroform is treated with anhydrous hydrogen chloride gas at 20 C. for 3 minutes, and then is kept at about 10 C. for 2 hours. The organic solution is washed with aqueous sodium acetate solution, then concentrated in vacuo to a residue which is crystallized from methylene chloride-pentane to give 9m-chloro-11o-hydroxyestradiol 3,17-diacetate.

EXAMPLE 16 9%] IB-Dicitloroeslradiol Diacylate A. 9a,]lfi-dichloraeszradiol diacezate. To a stirred,

aovasss cooled (--20 C.) solution of 9(l1)-dehydroes'tradiol diacetate (354 mg.) in methylene chloride (15 ml.) and pyridine (0.4 ml.) is added chlorine (78 mg.) in carbon tetrachloride (1.5 ml). The solution is stirred for 15 minutes at 20 (3., and for an additional hour at room temperature. The reaction mixture is then poured into water (300 ml.) the organic layer separated and washed successively with normal aqueous sodium thiosulphate, aqueous sulphuric acid, 10% aqueous sodium bicarbonate, and water, dried (MgSo and distilled in vacuo to a residue which is crystallized from acetone-hexane to give 911,1lddichloroestradiol diacetate.

In a similar manner 9(11)-dehydroestradiol dicaproate and 9(11)-dehydroestradiol dipropionateare reacted with chlorine in carbon tetrachloride to give 9a,11/3-dichloroi estradiol dicap-roate and 9a,11, -dichloroestradiol dipropionate, respectively.

B. 9a,]15-dichl0r0estradi0l di'benzoate. Similarly,

9(11)-dehydroestradiol'dibenzoate (478 mg.) in methylene chloride m1.) and pyridine (4 ml.) is reacted with 78 mg. of chlorine in carbon tetrachloride (1.5 ml.) at C. in the manner described in Example 16A. The resultant product is isolated in the described manner and recrystallized from ether-pentane to give 9u,11,8-dichloroestradiol dibenzoate.

EXAMPLE 17 9a-Chloro-115-Flu0r0estradi0lDiacylate A. 904 chloro 11/8 fluoroestraa'iol diacetate. To a stirred solution of 9(11)-dehydroestradiol diacetate (354 mg.) in carbon tetrachloride (15 ml.) and pyridine (2 ml.) is added hydrogen fluoride (200 mg.) in chloroformtetnahydrofuran (3:1; 0.67 ml.) and N-chlorosuccinimide (146 mg). Stirring is continued for 20 hours, and the reaction mixture is poured into 5% aqueous sodiumcarbonate solution (150 ml.) and extracted with methylene chloride. The organic extract is washed successively with water, 5% aqueous sulphuric acid, N-sodium thiosulphate and water, dried (M5580 and evaporated in vacuo to a residue which is crystallized from ether-hexane to give 9u-chloro-1lfl-fluoroestradiol diacetate.

B. Que-ChlOrO-lIfl-flllOlOSll'tltliOl dibenz0ate.9(1'1)-dehydroestradiol dibenzoate is reacted with hydrogen fluoride and N-chlorosuccinimide in the manner of Example 17A to give 9a-chlor0'1le-fiuoroestradiol dibenzoate.

EXAMPLE 18 9a-Br0mo-1lfl-Fluoroestradiol Diacetate To a stirred solution of 9(11)-dehydroestradiol diacetate (354 mg.) in diethylacetic acid (15 ml.) is added N- bromoacetamide (152 mg.) followed immediately by hydrogen fluoride (200 mg.) in a solution of chloroformtetrahydrofuran (3:1; 0.67 ml). Stirring is continued for 18 hours and the reaction mixture is then poured into 10% aqueous sodium carbonate solution .(150 ml.) and extracted with methylene chloride. The organic extract is washed with 5% aqueous sodium hydroxide and water, dried (MgSOQ, and evaporated to a residue which is crystallized from acetone-hexane to give 9a-br0m0-.11,8-fluoroestradiol diacetate.

EXAMPLE 19 9a-Br0m0-1Iii-Chloroestradiol Diacetate To a stirred solution of 9(11)-dehydroestradiol diacetate (354 mg.) and lithium chloride (2.0 g.) in glacialacetic acid (15 ml.) is added N-bromoacetamide (152 mg.) followed at once by an anhydrous solution of hydrogen chloride (41 mg.) in tetrahydrofuran (0.3 ml). Stirring is continued for three hours and the reaction mixture is .then poured into Water (200 ml.) and filtered. The residue on the filter is washed with Water, dried and crystallized from ether-pentane to give 9e-bromo-1lfi-chloroestradiol diacetate.

1'0 EXAMPLE 2O Qa BrOmO-J Ifi-A cetoxyestradiol D iacetate To a stirred solution of 9(11)-dehydroestradioldiacetate (354 mg.) and lithium acetate (1.5 g.) in glacial acetic acid (15 ml.) is added N-bromoacetamide (152 mg), The reaction mixture is stirred for 18 hours at room temperature and is then poured into water (150 1111.). The resultant precipitate is filtered, dried, and crystallized from acetonehexane to give 9a-bromo-l lfl-acetoxyestradiol diacetate (9a-bromo-l,3,5(l0)-estratriene-3, 11,6,1713-triol triacetate).

Similarly, 9(l1)-dehydroestradiol dibenzoate is reacted with N-bromoacetamide and lithium acetate in acetic acid to give 9 u-bromo-1lfi-acetoxyestradiol dibenzoate (9abromo-1,3,5(10)-estratriene 3,11fi,l7,8 triol ll-acetate 3,17-dibenzoate).

EXAMPLE 21 Qw-Chloro-l Jfl-Formyloxyeslradiol Diacetate To a stirred solution of 9(11)-dehydroestradiol diacetate (354 mg.) in formic acid (20 ml; 98%) containing sodium formate (2.0 g.) is added N-chlorosuccinimide (146 mg.) and a solution of hydrogen chloride (41 mg.) in tetrahydrofuran (0.3 ml). The mixture is stirred for 18 hours at room temperature and is then poured into water (200 ml;). The resultant precipitate is filtered, washed with water, dried and crystallized from acetone-hexane to give 9a-chloro'11,8-formyloxyestradiol diacetate (9achloro-1,3,5(10)-estratriene 3,115,175 triol ll-formate 3,17-diacetate).

EXAMPLE 22 9a,I1B-Dihal0gen0estrone M ethyl Ether A. 902-611ZOrO-IIfl-flI/IOIOESZI'OHG methyl etlter.-A solution of 9(11)-dehydroestrone methyl ether (282 mg.) in

carbon tetrachloride (15 ml.) and pyridine (2 ml.) is reacted with hydrogen fiuoride (200 mg.) and N-ch'lorosucwcinimide (.146 mg), in the manner of Example 17 to give 9a-chloro-1lfi-fiuoroestrone methyl ether (9ot-chloro-ll 3- fluoro-1,3.5(10)estratriene-3-ol-17-one 3-rnethyl ether).

B. 9a-brom0-J I fi-fluoroestrone methyl ether.-A solution of 9(11)-dehydroestrone 3-methyl ether (282 mg.) in diethyl acetic acid (15 ml.) is reacted with N-bromoacetamide (152 mg.) and hydrogen fluoride (200 mg), in the manner of Example 18, to give 9a-bromo-llfl-fiu0roestrone methyl ether.

C. Qa-bromo-Hfl-chloroeslrone methyl ether.-A solution of 9(11)-dehydroestrone 3-methyl ether (282 mg.) in glacial acetic acid (15 ml.) is reacted with N-bromoacetarnide (152 mg.) and hydrogen chloride (41 mg.) in the presence of'lithium chloride (2.0 g.), in the manner of Example 19, to give 9tx-bromo-1lfi-chloroestrone B-methyl ether.

D. 9st,]JB-diclzloroestrone methyl ether.--A solution of 1.0 g. of 9(11)-dehydroestrone methyl ether in carbon tetrachloride is allowed to react with 270 mg. of chlorine in the presence of pyridine according to the procedure of Example 9. The resultant product is crystallized from methylene chloride-pentane to give'9a,1lfi-dichloroestrone 3-methy1 ether.

EXAMPLE 23 A solution of 9(11)-dehydroestrone 3-methyl ether (282 mg.) in glacial acetic acid (15 ml.) is reacted with N- bromoacetamide (152 mg.) in the presence of lithium acetate (2 g.) in the manner of Example 20, to give 9abromo-l lfl-acetoxyestrone 3-rnethyl ether.

EXAMPLE 24 9(1] -Dehydr0eslradiol 3-Benzoare To a solution of 1.5 g. of 9(1l)-dehydroestrone benzoate iIl'lQQ ml. of tetrahydrofuran is added a solution of 740 mg. of sodium borohydride in 3 ml. of water. The

acreage 11 and the solution acidified with acetic acid. The resulting precipitate is filtered, washed, dried, and crystallized from acetone-hexane to give 9(1l)-dehydroestradiol S-benzoate, Ml. 193-194" (3.; [e1 +104 (dioxane).

EXAMPLE 25 912,1 lfi-Dichloroestradiol 3-Benzoate and the 17-Acetate Ester Thereof A. 9a,]Ifl-dichloroestradiol 3-benzoate.9(11)-dehydroestradiol 3-benzoate (250 mg.) is reacted with 49 mg. of chlorine in the presence of pyridine according to the procedure of Example 9. The resultant product is crystallized from methylene chloride-pentane to give 9ot,ll,8- dichloroestradiol 3-benzoate (901,1 lfi-dichloro-1,3,5( 10)- estratricne-3,17fi-diol 3-benzoate).

B. 9a,]1,8-dichl0r0estradiol-3-benz0ate 17-acetate. The compound of Example 25A (100 mg.) is acetylated with acetic anhydride in pyridine according to the procedure of Example 1113. The resultant product is crystallized from methylene chloride-pentane to give 90:,116- dichloroestradiol 3-henzoate l7-acetate (9a,11,S-dichloro- 1,3,5 l)-estratriene-3,l7,8-diol 3-benzoa-te l7-acetate).

EXAMPLE 26 9a-Chl0ro-1 1 fi-FhtoroJ 7a-Ethinylestmdiol 3 -M ethyl Ether 9a-chloro-1lfi-fluoroestrone methyl ether (200 mg.) in dimethyl sulfoxide is reacted with sodium acetylide according to the procedure of Example 10 and the resultant product is isolated and purified as described to give 9achloro-1lfl-fiuoro-17cx-ethinylestradiol S-methyl ether (90;- chloro 11B fiuoro-l7ot-ethinyl-1,3,5(10)-estratriene-3, 17(3-diol 3-methyl ether).

EXAMPLE 27 1-Mezhyl-9U1 )-Dehydr0str0ize Methyl Ether A. 1-methyl-9(I1)-dehydrostr0ne.-To a solution of 1.0 g. of 1,4,9(11)-androstatriene-3,17-dione in 40 ml. of acetic anhydride is added 250 mg. of p-toluene-sulfonic acid. The mixture is flushed with argon and heated on the steam bath for 5 hours, then poured into ice-water and stirred to hydrolyze any excess anhydride. The resulting 1 methyl-1,3,5-(l0),9(11)-estratetraene-3-ol-l7- one acetate is dissolved in 20 ml. of methanol, then a solution of 1 g. of potassium hydroxide in 2 ml. of water is added and the mixture heated under reflux for 20 minutes. The solution is poured into ice-water and acidified with hydrochloric acid. The resulting precipitate is filtered, washed with water, dried and crystallized from etherhexane to give l-methyl-9(11)-dehydroestrone, MP.

1X52 215 m (c- 241,l00), 253 I111t 12,100); [obi-245 (CHCla) B. 1 -methyl'-9(1l )-dehydr0str0ne methyl ether.To a solution of 500 mg. of the compound of Example 27A in ml. methanol is added a solution of 3 g. potassium hydroxide in 5 ml. of water. The mixture is chilled and 2 ml. of dimethyl sulfate is added dropwise, then the mixture is stirred at room temperature for /2 hour. Additional 2 ml. portions of dimethyl sulfate are added at the next two /2 hour intervals, then the mixture is stirred at final /2 hour, and allowed to evaporate overnight. The resultant residue is washed with water, dried, and crystallized twice from ether-hexane to give 1-methyl 9(11)-dehydrestrone methyl ether; MP. 100-102 C.;

W52 213 m (6 31,300), 252 m (c- 17,300);[o1] +262 (CHCla) EXAMPLE 28 1-Methyl-9 (11 )-D ehydrosti'one Acetate To a solution of 250 mg. of 1-rnethyl-9(11)-dehydroestrone in 5 ml. of pyridine is added 1 ml. of acetic anhydride and the mixture is allowed to stand at room temperature for 22 hours. The mixture is then poured into ice-water, stirred to hydrolyze the excess anhydride and allowed to crystallize. The resultant solid is filtered and recrystallized from ether to give l-methyl-9-(11)-dehydrostrone acetate, M.P. 125-126" C.;

max.

( CHCh) EXAMPLE 29 1-Methyl-9(1Z -Dihal0gen0estr0n Methyl Ether A. 1-methyl-9c'.,1lfi-dichloroestrone methyl ethetc-A solution of l-methyl-9(ll)-dehydrostrone 3-rnethyl other (296 mg.) in carbon tetrachloride (15 m1.) and pyridine (0.4 ml.) is reacted with chlorine (78 mg), in the manner of Example 9, to give 1-methyl-9a,llfi-dichloroestrone methyl ether.

B. 1 methyl 9a. bromo-lIfi-fluoroestrone methyl ether.-A solution or: 1-metl1yl-9(ll)-dehydrostrone 3- methyl (296 mg.) in diethyl acetic acid (15 ml.) is reacted with N-bromoacetamide (152 mg.) and hydrogen fluoride (200 mg), in the manner of Example 18, to give 1-II1Btl1Y1-90t-bl'0fl10-1Lia-11110106830116 methyl ether.

C. 1 methyl 9a bromo 11,8 chloroestrone methyl ether.-A solution of 1-metl1yl-9(11)-dehydroestro 3- methyl ether (296 mg.) in glacial acetic acid (15 ml.) is reacted with N-bromoacetamide (152 mg.) and hydrogen chloride (41 mg.) in the presence of lithium chloride (2.0 g), in the maner of Example 19, to give l-methyl- 9ot-bromo-1lfi-chloroestrone methyl ether.

EXAMPLE 30 1 -M ethyl-9a-Brom0-I 1 5-11 y droxy estrone Methyl Ether A solution of 500 mg. of 1-methyl9(11)-dehydroestrone methyl ether in dioxane is reacted with 240 mg. of N-bromoacetamide in the presence of water and perchloric acid according to the procedure of Example 13. The resultant product is crystallized from methylene chloride-pentane to give 1-methyl-9m-bromo-1lfi-hydroxyestrono methyl ether.

By subjecting the compound of this reaction to the sequence of reactions as described in Example 6 there is obtained 1-methyl-9B,1l,B-oxidoestrone methyl ether from which is derived l-methyl-9a-iluoro-1lfi-hydroxyestrone methyl ether and l-methyl-9et-chloro-1lfl-hydroxyestrone methyl ether.

EXAMPLE 31 1 -Methyl-9ot-Chl0r0 -1 1,8-Fluor0estr0ne 3-A cetate A solution of 1-methyl-9(11)-dehydroestrone 3-acetate (324) mg.) in carbon tetrachloride (15 ml.) and pyridine (2 ml.) is reacted with hydrogen fluoride (200 mg.) and N-chlorosuccinimide (146 mg), in the manner of Example 17, to give 1-rnethyl-9ot-chloro-1lfi-fluoroestrone B-acetate.

EXAMPLE 32 I -Methyl9 a-Bromo-I JB-Hydroxyestrorze Acetate A solution of 25 0 mg. of 1-methyl-9(11)-dehydroestrone acetate in dioxane is reacted with 110 mg. of N-brornoace'tamide in the presence of water and perchloric acid according to the procedure of Example 13. The resultant product is crystallized from methylene chloride-pentane to give 1-methyl-9u-bromo-1lfi-hydroxyestrone 3 acetate.

EXAMPLE 3 3 1 JJethyl-Qa-Fluoro-J J p-Hydroxyestrone Acetate A. l-methyl-9,8,11fl,0xid0estr0ize acetate-A solution of 200 mg. of 1-methyl-9ot-bromo-l lfi-hydroxyestrone acetate in acetone is heated with potassium acetate according to the procedure of Example 6A. The resultant product is crystallized from acetone-hexane to give 1-methyl-9,B,ll,6- oxidoestrone acetate.

B. 1-methyl-9ot-flu0r0-1Zfi-hydroxyestrone acetate-A solution of mg. of the compound of Example 33A lized from acetne-hexane to 'give l-methyl-9a-fiuoro-l 118- hydroxy-l7oe-ethinylestradiol 3-acetate.

EXAMPLE 35 l-Methyl-fll] Dehydroestrarliol (hid the 3,17-Di- Lower Alkz'moate's Thereof A. 1-methyZ-9(1J )Dehydroeszradiol.-A solution or 2.5 g. of l-methyl-9(1l)-dehydroestr0ne (compound 27A) in 50 'mhof methanol is chilled in ice. To the chilled s'oiutidn 2.5 g. or" sodium borohydrideis added in portions and the resulting solution keptat 0 C. until foaming subsides. It is then allowed to stand at room temperature for 1 hour, acidified with 5% hydrochloric acid and diluted with water. The resulting product is crystallized from aqueous acetone to give 1 methyl-9(11)-dehydroestradiol,

MP. 148-152 C.;

. stag ers m 25,000), 253m (e 13,200); [ab-P138 (CHCl B. 1-methyZ-9(11 )dehydroest'radiol diacetaie;-'-A solution of 1.5 g. of the compound of Example 35A in ml.

carefully poured into cold 10% ammonium sulphate solution (200 ml.). The aqueous mixture is extracted with methylene chloride, and the organic extracts washed with Water, dried (Na SO and evaporated to a residue which is crystallized from acetone-hexane to give 17wmethy1- 9(l1)-dehydroestradiol S-methyl ether.

By following the above procedure, but substituting ethyl magnesium bromide (from ethyl bromide and magnesium metal in ether) for methyl magnesium iodide, the corresponding l7a-ethyl compound is prepared, i.e., 17a-ethyl- "9 (l1)-dehydroestradiol 3-methyl ether.

EXAMPLE 39 I,17a-Dfmethyl-9(11)-Dehydroeslradi0l 3-Methyl Ether 1-rnethyl-9(11)-dehydroestrone 3-methyl ether is reacted with methyl magnesium iodide in a manner similar to that described in Example 38 to give 1,1.7a-dimethyl- 9(1 l)-dehydroestradiol 3-methyl ether.

Similarly by utilizing ethyl magnesium bromide instead of methyl magnesium iodide in the above reaction, there is obtained 1-methy1-17a-ethyl-9(1l)-dehydroestradiol 3- methyl ether.

of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours, and is then poured into ice-Water. The resulting precipitate is filtered and dried and crystallized twice from ether-hexane to give 1-'methyl-9(11)-dehydroestradiol diacetate, MP. 128- 129 C.; [111 +78 (CHClg).

C. In a similar manner, by substituting other lower alkanoic acid anhydrides, such as propionic and valeric acid anhydrides, for acetic anhydride in the above procedure, there are obtained the corresponding 3,17-dilower alkanoates, i.e., the 3,17-dipropionate and the 3,17- ctliivalerate, respectively, of lmethyl'-9(11)-dehydroestraiol.

EXAMPLE 36 1 -Methyl-9a,1 J fi-Dichloroestradiol Dipropionate A solution of 300 mg. of 1-rnethyl-9(1l)dehydroestradiol dipropionate in carbon tetrachloride is reacted with 55 mg. of chlorine in the presence of pyridine according to the procedure of Example 9 to give l-methyl-9a,ll,B- dichleroestr'adiol dipropionate.

EXAMPLE 3 7 1-2li'ethyl-9a-Brom0-1 1 ,e-Hydroxy estradiol 3,] 7-Diaeetate A solution of 1-methyl-9(ll) dehydroestradiol diacerate (200 mg.) in dioxane is allowed to react with 80 mg. of N-bromo-acetamide in the presence of water and perchloric acid in the manner of Example 13 to give 1- methyl-9wbromo-l l fi-hydroxyestradiol 3,17-diacetate.

EXAMPLE 3s '1 7a-Methyl-9(1l )-Dehydr0eslradiol S-Methyl Ether To 'a stirred ethereal solution of methyl magnesium iodide (generated from magnesium metal (3 g.) and methyl iodide (7.5 ml.) is anhydrous ether (200 ml.)) is added a solution of 9(ll)-dehydr0estrone 3-methyl ether (1.0 g.) in tetrahydrofuran ml.) dropwise, with stirring. The reaction mixture is then diluted by the addition of tetrahydrofuran (150 ml.), and the stirred mixture is distilled until 200 m1. ofdi'stillate has been collected. The

reaction mixture is refluxed for one hour, cooled, and

EXAMPLE 40 1 7a-Met hyl-9U1 -Dehyclroestradiol and the l -M ethyl Analog Thereof A solution of 9(11)-dehydroestrone (2 g.) in tetrahyd-rofuran ml.) is reacted with an ethereal solution of methyl magnesium iodide (prepared from magnesium metal (6 g.) and methyl iodide (15 ml.) in anhydrous ether (400 ml.)) in the manner of Example 38, to give l7e-methyl-9(11)-dehydroestradiol.

In a similar manner, 1-methyl-9(ll)-de:hydroestrone (the compound of Example 27A) is reacted with methyl magnesium iodide to give 1,l7o;-dimethyl-9(11)-dehydroestradiol.

EXAMPLE 41 17u-Elethyl-9U1)-Dehya'roestradiol 3-Acetate and the J-Methyl Analog Thereof One gram of 17u-rnethyl-9(ll)-dehydroestradiol is al lower to react with acetic anhydride (1 ml.) in pyridine (10 ml.) at room temperature for 18 hours. The reaction mixture is diluted with Water and the resultant preci'pitate filtered, washed with water, and dried to give cmethyl-L 11)-dehydroestradiol 3-acetate.

In a similar manner, 1,l7cdimethyl-9(11)-dehydroestradiol is reacted with acetic anhydride and pyridine to give 1,17a-dimethyl-9(l1)-dehydroestradiol I3-acetate.

EXAMPLE 42 904,1 lfl-Dichloro l 7or-Meihylestradiol 3-Methyl Ether A solution or" two hundred and ninety eight milligrams of 17wmethyl-9(1l)-dehydroestradiol 3-methy1 ether in carbon tetrachloride (15 ml.) and pyridine (0.4 ml.) is allowed to react with chlorine (78 mg.) in the manner of Example 9, to give 905,1lp-dichloro-l7a-methylestradiol B-methyl ether.

In the same manner, but using as starting material 17aethyl-9( l1)-dehydroestradiol 3-methyl ether (Example 38) there is obtained 9c4,l1,8-dichloro-l7a-ethylestradiol 3-methy1 ether.

EXAMPLE 43 1,1 7c .-Dimethyl-9a,1 1 fl-Dz'chloroestradiol 3-M ethyl Ether A solution of three hundred and twelve milligrams of 1,l7c ,dimethyl-(1l)-dehydroestradiol 3-methyl ether in methylene chloride (15 m1.) and pyridine (0.4 ml.) is allowed to react with chlorine (78 mg.) in the manner of Example 16A to give l,l7a-dimethyl-9o,1lfi-dichloroestra iol S-m'ethyl ether.

Similarly, by utilizing 1-methyl-l7a-ethyl-9(11)-dehydroestradiol -3-methyl ether as starting compound in the procedure of this example, there is obtained l-methyl-9oe, llfl-dichloro-l7ct-ethylestradiol 3-methyl ether.

EXAMPLE 44 QoL-BI'O-lTlO-J 1 3- iytlroxy-l 7 -M ethylcstrad z'ol S-Methyl Ether and the I-Methyl Analog Thereof A solution of five hundred milligrams of Not-methyl- 9(l1)-dehydroestradiol 3-methyl ether in dioxane (50 ml.) is allowed to react with N-bromoacetarnide (242 mg.) in water (5.8 ml.) and 1.5 N-perchloric acid (2.3 ml.), in the manner of Example 13, to give 9u-bromo-llflhydroxyestradiol 3-rnethyl ether.

In a similar manner, l,17a-dimethyl-9(11)-dehydroestradiol B-methyl ether is reacted with N-bromoacetamide and erchloric acid to give 1,l7o -dimethyl-9abromo-lll3-hydroxyestradiol 3-1nethy1 ether.

EXAMPLE 45 ot-FZMOIO-Z J B-Hya'roxyJ 7ot-Methylestradiol 3 -M eth yl E ther A. 95,] l ,8-oxid-17a-metlzylesiradiol 3-methyl ether.- A solution of 300 mg. of 9abromo-1ldhydroxy-lhmethylestradiol S-methyl ether in acetone (20 ml.) is al lowed to react with potassium acetate (600 mg.) in the manner of Example 6A to give 9B,l1 [3-oxido-l7 a-methylestradiol 3-methyl ether.

3. 9a-flll0iO-1 1 ,B-hydrmy-I 7a-n'zelhylestradi0l fi-mcihyl ether.-A solution of live hundred milligrams of 93,115- oxido-l7a-mcthylestradiol 3-methyl etier (the compound of Example 45A) in methylene chloride (20 ml.) is allowed to react with 48 percent aqueous hydrofluoric acid (2 ml.) in the manner of Example 63 to give 9m-fiuoro- 1lfi-hydroxy-l7a-methylestradlol 3-methyl ether.

Similarly, by subjecting 1,17ot-dimethyl-9a-bromo-llohydroxyestradiol 3-methyl ether to the sequence of reactions of Examples 45A and B, there is obtained 1,17adimethyl-9et-fluoro-l lfi-hydroxyestradiol 3-methyl ether.

EXAMPLE 46 9 oz-Cltl0r0-l 1 fl-Fluoro-J 7 WM 6111 yl Estract'iol 3 -A cetate A solution of three hundred and ten milligrams of 17a-methyl-9(ll)-dehydr0estradiol 3-acetate in carbon tetrachloride ml.) and pyridine (2 ml.) is allowed to react with hydrogen fluoride (200 mg.) and N-chlorosuccinimide (146 mg.) in the manner of Example 17 to give 9u-chloro-1lfl-fiuoro-l'le-methylestradiol 3-acetate.

EXAMPLE 47 A solution of five hundred milligrams of 1,17ct-dimethyl-( ll)-dehydroestradiol 3-acetate (the compound of Example 41) in dioxane (50 ml.) is allowed to react with N-bromoacetamide (213 mg.) in water (5.0 ml.) and 1.5 N-perchloric acid (2.0 ml.) in the manner of Example 13 to give 1,l7a-dimethyl-9d-bromo-llB-hydroxyestradiol Z-acetate.

EXAMFPLE 48 1-Methyl-9a-Br0mo-1lfl Acezoxyestrone 3-Methyl Ether 1-methyl-9(ll)-dehydrostronc 3-methyl ether in glacial acetic acid is reacted with llbromoacetamide in the presence of lithium acetate in a manner similar to that described in Example 20 to give l-rnethyl-9ot-brcmo-llflacetoxy 3-methy1 ether.

EXAME'LE 49 1 Methy!-9ot,l1 ,B-Dichloro-l'lwEthit tylestradiol 3-Mefhyl Ether l-methyl-9ea1lfl-dichloroestrone 3-rnethyl ether (prepared as described in Example 29A) is reacted with sodium acetylide in dimethyl sulfoxide in the manner described in Example 10, The resultant product is isolated 15 in the described manner to give l-methyl-9a,ll 3-d ichloro-l7oc-ethinylestradiol 3-methyl ether.

In a similar manner, 9a-chloro-l1 ,B-hydroxyestrone S-acetate the compound of Example 6), 9a-bIOn'l0-1l/3- acetoxyestrone 3-methyl ether (compound of Example 23) and l-methyl-9a-bromo-ll/3-acetoxyestrone B-methyl ether (the compound of Example 48) are each reacted with sodium acetylide in dimethylsulfoxide in the manner of Example 10 to give respectively 9u-chloro11fl-hydroxy-17ot-ethinylestradiol 3-acetate, 9u-bromo-ll/3-acetoxy-l7a-ethinylestradiol 3-rnethyl ether and l-rnethy1-9abromo-l lfl-acetoxy-l7a-ethinylestradi0l S-methyl ether, respectively.

EXAMPLE 5'0 9C6-BIOl710-11-KElO-1 7ot--1-.4'ethylestradi0l 1 7-14 cetate and the I-Methyl Analog Thereof A. 17ot-meihyl-9(11)-dehydr0estradi0l diacetate.-To 1 gram of l7ct-methyl-9(1l)-dehydroestradiol (the com.- pound of Example 40-) in 10 ml. of pyridine is added 2 m1. of acetic anhydride. The reaction mixture is heated on the steam bath for 48 hours then cooled. Water is added and the aqueous mixture is extracted with ether. The extracts are combined, washed with 2 N hydrochloric acid and then with water, dried over sodium sulfate and evaporated in vacuo to a residue substantially of l7u-methy1-9 l l)-dehydroestradiol diacetate.

in a similar manner, l,l7a-dimethyl-9(ll)-dehydroestradiol is reacted with acetic anhydride in pyridine to give 1,l7a-dimethy1-9(ll)-dehydroestracliol diacetate.

B. 9a-br0m0-Z1fl-hydroxy-J 7a-methylestradiol 3,17-a'iacetate-IM-methyl-M11)-dehydroestradiol diacetate is reacted with N-bromosuccinimide and perchloric acid in a manner similar to that described in Example 4. The resultant product is isolated in the described manner to give 9a-bromo-llfi-hydroxy-l7u-methylestradiol 3,17diacetate.

Similarly, 1,l7a-dimethyl-9( l 1 -del1ydroestradiol diacetate is reacted with N-bromosuccinimide to give 1,17adimethyl-9ot-bromo-1lB-hydroxyestradiol 3,17-diacetatc.

C. 9wbr0mo-1Z-ket0-I7o-metltylestmdi0l diacetata- 9a-bromo-l lfihydroxy- 1 7cz-methylestradiol 3,17-diacetate reacted with chromic acid-sulfuric acid reagent in the manner described in Example 8. The resultant product is isolated as described to give 9e-bromo-1l-lteto-l7en ethylestradiol diacetate.

Similarly, l,l7a-dimethyl-9a-bromolfi-hydroxyestradiol 3,17-diacetate is reacted with chromic acid-sulfuric acid reagent to give l,17wdin1ethyi--9ccbromo-ll-ketoestradiol diacetate.

D. 9m-br0m0-11-ket0-1 7oa-methyleslradz'ol 17-(tcetate.- A solution of 1 gram of QwbrcmodI-Reto-l'la-methylestradiol diacetaie in 30 ml. of 1% potassium carbonate in tl% aqueous methanol is left at room temperature for 2 hours. The solution is diluted with water. A solid separates which is filtered, dried, and crystallized from acetone-hexane to give 9e-bromo-l1l7ct-methylestradiol l7-acetate.

Similarly, l,17ct-dimethyl-5o-bromo-1l-ketoestradiol diacetate is hydrolyzed with 1% potassium carbonate in aqueous methanol to give l,l7u-dimethyl-9m-bromo-l lketoestradiol 17-acetate.

EXAMPLE 5 1 9e--H rzlogerzo-l 1 -Ketoes1rediol Derivatives 1 7 with 1% potassium hydroxide in 90% aqueous methanol at room temperature for 24 hours yielding 9a-ehloro-11- ketoestradiol.

EXAMPLE 52 1 Methyl 9a Fluoro 11 Keto 17a Ethinylestradial 3 -Methyl Ether and 9a Fluoro 11 -Ket- 17a- Etlzinylestradiol 3-Acetate 'A. I-methyl-9a-flu0r0-1J-ketoeslrone 3-melhyl ether.- In a manner described in Example 8, l-methyl-h-fiuorollfi-hydroxyestrone 3-methyl ether (prepared as described in Example 30) is reacted with chromic acid-sulfuric acid reagent and the resultant product isolated to give l-methyl-9u-fiuoro-1l-ketoestrone 3-methyl ether.

B. 1 methyl 9oz fluoro l1 keto 17o: ethinylestradiol 3-methyl ether.-In a manner similar to that described in Example 10, 1-methyl-9a-fiuoro-1l-ketoestrone S-methyl ether is reacted with sodium acetylide in dirnethylsulfoxide and the resultant product isolated and purified to give 1-methyl9a-fluoro-1 l-keto-17aethinylestradiol 3-methyl ether.

In a similar manner, 9a-fiuoro-11-ketoestrone 3-acetate (the compound of Example 8) is reacted with sodium acetylide in dimethylsulfoxide and the resultant product isolated and purified to give 9ot-fluoro-11-keto-17a-ethinylestradiol 3-acetate.

EXAMPLE 53 9a-Br0mO-1 I ,S-A cetoxy-l 7 rx-M ethylestradiol 3-Acetate EXAMPLE 54 1-Methyl-9u-Br0m0-11,8-Acetoxyestradiol S-Benzoate A. 1-mezhyl-9(11)-dehydr0estr0ne 3-benz0ate.-In a manner similar to that described in Example 2, l-methyl- 9(1l)-dehydroestrone (the compound ofExample 27A) is reacted with benzoyl chloride in pyridine and the resultant product isolated to give 1-methyl-9(11)-dehydro'- estrone 3-benzoate.

B. 1-methyl-9(11)-dehydr0estraa'iol 3-benz0ate.-In a similar manner to that described in Example 11A l-methyl-9(11)-dehydroestrone 3-benzoate in methanol is reacted with sodium borohydride and the resultant product isolated as described to give 1-methyl-9(11)-dehydroestradiol S-benzoate.

C. 1 methyl 9a bromo 11d acetoxyestradfol 3-benzoate-In the manner of Example the 9(11)- dehydroestradiol of Example 543 is reacted with N- brornoacetamide and lithium acetate in glacial acetic acid and the resultant product isolated as described to give 1- methyl-9a-bromo-1 1 ,B-acetoxyestradiol-B-benzoate.

200 mg. of 9e-fluoro-1lp-hydroxyestradiol 3,17-diacetate (the compound of Example 13) is dissolved in 10 ml. of a 1% solution of potassium carbonate (prepared from 1 gram of potassium carbonate in 90 ml. methanol and 10 ml. water). The solution is left at room temperature for 90 minutes, then water is added. A solid separates which is filtered, washed with water, then dried to give 9ot-fluoro-1lfl-hydroxyestradiol 17-acetate.

In a similar manner other estradiol diacetates may be converted to the corresponding 3-ol-17-acetate as, for example, 1-rnethyl-9a,1lfi-dichloroestradiol diacetate (the compound of Example 36) upon reaction with potassium carbonate in methanol in the above described manner yields 1-methyl-9a,1lfi dichloroestradiol 17-acetate.

EXAMPLE 56 9ot-Chlor0-11fl-Flu0roestradiol 1 7 -Benz0ate 200 mg. of 9a-chloro-1lp-fluoroestrad-iol di-benzoate (the compound of Example 18) is dissolved in 10 ml. of a 1% solution of potassium carbonate (prepared from 1 gram of potassium carbonate in ml. of methanol and 10 ml. of water). The solution is left overnight at room temperature then water is added. A solid separates which is filtered, washed with water and dried to give 9a-chloro- 11fl-fiuoroestnadiol 17-benzoate.

EXAMPLE 57 1 -MethyI 9a-Br0m0-1 Ifi-A cetoxyestradia-l 3-Benzoate v 17-Hemisuccinate To 1 gram of I-methyl-Qa-bromo-llfl-acetoxyestradiol 3-benzoate (the compound of Example 54) in 10 ml. of pyridine is added 1 gram of succinic anhydride. The re action mixture is heated on a steam bath for 1 hour then cooled and diluted with water. A solid separates which is filtered, washed with water and dried to give l-methyl- 9a-bromo-1lp-acetoxyestradiol 3-benzoate 17-hemisuccinate.

EXAMPLE 58 9a-Chl0r0-1I-Ketoestradiol 3,17-Di-Hemisuccinate and the Sodium Salt Thereof A. 9a-chloro-1 1 -ketoestradiol 3,1 7 -di-hemrisuccinate.- In a manner described in Example 57 9a-ch1oro-11-ketoestradiol (the compound of Example 518) is reacted with succinic anhydride in pyridine and the resultant product isolated to give 9a-chloro-11-ketoestradiol di-hemisuccinate.

B. 9a-chl0r0-1I-ketaestradiol 3,17-di-sodium hemisuccinate.T0 1 gram of 9a-chloro-1l-ketoestradiol 3,17-dihemisuccinate suspended in ml. of water is added 4.08 ml. of a 10% aqueous solution ofsodium hydroxide. The resultant'aqueous solution is evaporated in vacuo to a residue of substantially 9a-Ch1010-1 1-ketoestradiol 3,17-disodium hemisuccinate. l

EXAMPLE 59 9a,] I ,B-Dichloroestrone 9a,llfi-dichloroestrone 3-acetate (the compound of Example 3) is left overnight atfroom temperature with a 1% solution of potassium carbonate in a manner similar to that described in Exainple'SG. I The resultant product is isolated in the manner describedto give 90:,11/i-dichloroestrone.

In a similar manner, other esters may be hydrolyzed to the corresponding free-hydroxy compound. For example, 9a,llfi-dichloro-17a-ethinylestradiol S-benzoate (the compound of Example 10) and 90L-flUOI'O-11fi-hy? droxyestrone 3-a cetate (the compound of Example 63) areeach left overnight with 1% potassium carbonate and the respective resultant products isolated to give respectively 91:,1lp-dichloro-17a-ethinylestradiol and 9a-fluoro- 1 1 fi-hydroxyestrone.

EXAMPLE 60 9a,1I{3-Dichlor0estr0na 3-Sulfa te and the Potassium Salt Thereof A. 9d,]Ifl-dichloroestrone 3-potasst'um sulfate.-A mixture of 1 gram of 9a,11fi-dichloroestrone (the com- 7 pound of Example 59) and 1 gram of pyridine-sulfur tri oxide complex in 10 ml. of pyridine is stirred at room temperature for 2 /2 hours. The mixture is then cooled in an ice bath and 1 ml. of 50% aqueous potassium hydroxide added rapidly with vigorous stirring. The mixture is stirred 2 minutes longer then allowed to cool to room temperature without stirring. The resultant twophase system is centrifuged at room temperature and the pyridine layer decanted. The aqueous residue is washed with pyridine and the pyridine washis combined with the original pyridine layer. Ether is then added to the stirred pyridine solution until precipitation is complete. The mixture is then filtered and the residue dried to give substantiaily 9a,11/8-dich1oroestrone 3-potassium sulfate.

B. 9a,]lfl-dic'lzloroestrone 3-sulfate.-0.5 gram of the 3-potassium sulfate ester of Example 60A is dissolved in 50 ml. of water and the solution brought to neutrality by adding hydrochloric acid. A solid results which is filtered and dried to give 904,11fl-dlhl0f068i10t16 I i-sulfate.

In a similar manner, other estratrienes of our invention may be converted to the sulfate ester. Thus, for example, 9a-chloro-1lfi-fiuoroestrad-iol 17-benzoate (the compound of Example 56) upon reaction with pyridine-sulfur dioxide complex and isolation of the resultant product as described to give 9a-chlo1'o-1lfl-fluoroestradiol 3- potassium sulfate 17-benzo-ate which is neutralized with hydrochloric acid "to give 9a-chloro-1lfi-fluoroestradiol 3-sulfate 17-benzoa-te.

EXAMPLE 61 9a,] I/S-Dz'chloroestradiol To 500 mg. of 901,1lfi-dichloroestradiol diacetate (the compound of Example 16) is added 20 ml. of 1% potassium hydroxide in 90% aqueous methanol. The solution is left at room temperature for 24 hours, then diluted with water and made slightly acid by the addition of dilute hydrochloric acid. The resultant precipitate is filtered, washed with water, dried, and recrystallized from methylene chloride-pentane to give 9a,11fl-dichloroestradioL Similarly, other 17-acylate esters are hydrolyzed to the corresponding free hydroxy compound. For example, 9u-fluoro-llB-hydroxyestradiol dipropionate and l-methyl-9a,1lfl-dichloroestradiol 17-acetate are each hydrolyzed with 1% potassium hydroxide in aqueous methanol to give respectively 9a-fluoro-1lp-hydroxyestradiol and 1-methy1-9a,1 l ,B-dichloroestradiol.

We claim:

1. A compound selected from the group consisting of 1,3,5 ()-estratrienes having the following structural formula:

Z ll

wherein R is a member selected from the group consisting of H, lower alkyl, and an acid radical of an acid selected from the group consisting of sulfuric acid and carboxylic acids having up to 8 carbon atoms; W is a member selected from the group consisting of H and methyl; X is a halogen having an atomic weight less than 100; Y is a R being a member selected from the group consisting of 2Q H and lower alkanoyl and X being a halogen of atomic weight less than 40 and when Y is X, the halogen X has an atomic weight greater than 20; and Z is a member selected from the group consisting of keto,

lower alkyl and oEoH R" being a member selected from the group consisting of H and lower alkanoyl.

2. Qa-X-l1B-X-1,3,5(10)-estratriene-3-ol-17-one wherein X is a halogen having an atomic weight greater than 20 and less than 100, and X is a halogen having an atomic weight less than 40.

3. 3-lower .aIkyloXy-Qa-X-I 1/3-X-1,3,5 10)-estratrienel7 one wherein X is a halogen having an atomic weight greater than 20 and less than 100, and X is a halogen having an atomic weight less than 40.

4. 3 OR X X 1,3,5(10) estratriene- 17-one wherein R is an acid radical of a carboxylic acid having up to 8 carbon atoms, X is a halogen having an atomic weight greater than 20 and less than 100, and X is a halogen having an atomic weight less than 40.

6. 9a,11fi3-dichl0roestrone acetate.

8. 9a-chloro-1lfl-fiuoroestrone 3-methyl ether.

9. 90 X -115 X 17a ethinyl 1,3,5(10) estratriene-3-ol-17-0ne wherein X is a halogen having an atomic weight greater than 20 and less than 100, and X is a halogen having an atomic weight less than 40.

10. 3 OR 90a X 11B -17Ct ethinyl (10)- estratriene-17-one wherein R is an acid radical of a carboxylic acid having up to 8 carbon atoms, X is a halogen having an atomic weight greater than 20 and less than 100 and X is a halogen having an atomic weight less than 40.

11. 3-lower alkyloxy-9a-X-11/3-X'-17a-ethiny1-1,3,5- (l0)-estratriene-l7-one wherein X is a halogen having an atomic weight greater than 20 and less than 100, and Xis a halogen having an atomic weight less than 40.

12. 9a,1lfl-dichloro-l7a-ethinylestradiol 3-benzoate.

13. 9a,1lfi-dichloro-17ot-ethinylestradiol.

14 9a chloro 11B fluoro 17oz ethinylestradiol 3-methyl ether.

15. 9a-X-1,3,5 10)-estratriene-3,11/9-diol-17-one wherein X is a halogen having an atomic weight less than 100.

16. 3 OR 9oz X 1,3,5(l0) estratriene 11,8 ol 17-one wherein R is an acid radical of a carboxylic acid having up to 8 carbon atoms, and X is a halogen having an atomic weight less than 100.

17. 3-lower alkyloxy-9a.-X-1,3,5 10)-estratriene-1 1,8-01- 17-one wherein X is a halogen having an atomic weight less than 100.

18. 9a-fluoro-1lB-hydroxyestrone B-acetate.

19. 9ot-X-11 3-X-estradiol wherein X is a halogen hav-- ing an atomic weight greater than 20 and less than 100,, and X is a halogen having an atomic weight less than 40.

20. 9m-X-ll 3 hydroxyestradiol wherein X is a halogen having an atomic weight less than 100. v

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3,076,829

February 5, 1963 Hans Reimann et all,

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected belowa a Column 20 line 37, for "-3oll7-one" read -3 l7B- dlol lines 41 and 47, for "l'Z-one" M 175- 1 I,

, each oceurJr-ence read Signed and sealed this 3rd day of September 1963,

EAL)

test:

{NEST w. SWIDER DAVID A D testing Officer Commissioner of Patents 

1. A COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF 1,3,5(10)-ESTRATRIENES HAVING THE FOLLOWING STRUCTURAL FORMULA: 